Identification of monomethylsulochrin as a novel agent to ameliorate DSS-induced ulcerative colitis through dual modulation of the IL-17/TNF pathway and gut microbiota.

Abstract

Novel therapeutic agents with improved safety and efficacy are urgently required for ulcerative colitis (UC), a refractory inflammatory bowel disease. Mangrove-derived natural products represent a promising reservoir for drug discovery. Monomethylsulochrin (MMSC) is a type II polyketide isolated from the endophytic fungus Aspergillus fumigatus of the mangrove plant Aegiceras corniculatum. However, its therapeutic effects on UC and the underlying mechanisms remain unclear. Herein, we evaluated the efficacy of MMSC by using a dextran sodium sulfate (DSS)-induced colitis mouse model and elucidated the underlying mechanisms by proteomics analyses, molecular biology techniques, and 16S rDNA gene sequencing. Our results demonstrated that MMSC significantly ameliorated DSS-induced colitis, as evidenced by reduced disease activity index, preserved colon length, and attenuated histopathological damage. Mechanistically, proteomics profiling and subsequent validation confirmed that MMSC concurrently suppressed the interleukin (IL)-17 and tumor necrosis factor (TNF) signaling pathways by downregulating key nodes (matrix metalloproteinase [MMP]-9, S100 calcium-binding protein A8 [S100a8], CCAAT/enhancer-binding protein beta [Cebpb], cAMP responsive element binding protein 1 [Creb1], and Fas) and related pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-17, TNF-α) in both colonic tissues and lipopolysaccharide (LPS)-stimulated NCM460 cells. Furthermore, MMSC restored gut microbial diversity and composition in mice with colitis, reversing DSS-induced dysbiosis. Spearman correlation analysis revealed that the IL-17/TNF pathway exhibited a notable correlation with MMSC-mediated restoration of the gut microbiota. In conclusion, MMSC alleviates UC through a dual mechanism integrating suppression of IL-17/TNF signaling and restoration of gut microbiota homeostasis, highlighting it as a promising candidate for developing novel therapies against UC.